M2, a novel anthracenedione, elicits a potent DNA damage response that can be subverted through checkpoint kinase inhibition to generate mitotic catastrophe

2011 ◽  
Vol 82 (11) ◽  
pp. 1604-1618 ◽  
Author(s):  
Benny J. Evison ◽  
Mile Pastuovic ◽  
Rebecca A. Bilardi ◽  
Robert A. Forrest ◽  
Paul P. Pumuye ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Mitotic Catastrophe ◽  
Kinase Inhibition ◽  
Checkpoint Kinase ◽  
Damage Response

DNA damage response protein checkpoint kinase 2 (CHK2) links chromosomal instability to cellular metabolism in hepatocellular carcinoma (HCC)

2020 ◽  
Vol 73 ◽  
pp. S639-S640
Author(s):  
Matteo Lulli ◽  
Veronica Ghini ◽  
Tommaso Mello ◽  
Caecilia Sukowati ◽  
Antonio Mazzocca ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Chromosomal Instability ◽  
Cellular Metabolism ◽  
Checkpoint Kinase ◽  
Damage Response ◽  
Checkpoint Kinase 2

scholarly journals Questioning the Role of Checkpoint Kinase 2 in the p53 DNA Damage Response

2003 ◽  
Vol 278 (23) ◽  
pp. 20480-20489 ◽  
Author(s):  
Jinwoo Ahn ◽  
Marshall Urist ◽  
Carol Prives
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Checkpoint Kinase ◽  
Damage Response ◽  
Checkpoint Kinase 2

scholarly journals Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells

2009 ◽  
Vol 8 (1) ◽  
pp. 45-54 ◽  
Author(s):  
Leslie A. Parsels ◽  
Meredith A. Morgan ◽  
Daria M. Tanska ◽  
Joshua D. Parsels ◽  
Brian D. Palmer ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Pancreatic Cancer Cells ◽  
Damage Response

scholarly journals DNA Methylation Inhibitor 5-Aza-2′-Deoxycytidine Induces Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by DNA Methyltransferases 1 and 3B

2007 ◽  
Vol 28 (2) ◽  
pp. 752-771 ◽  
Author(s):  
Stela S. Palii ◽  
Beth O. Van Emburgh ◽  
Umesh T. Sankpal ◽  
Kevin D. Brown ◽  
Keith D. Robertson
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Tumor Cells ◽  
Dna Damage Response ◽  
Dna Methyltransferases ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Checkpoint Kinase ◽  
Genome Wide ◽  
Damage Response

ABSTRACT Genome-wide DNA methylation patterns are frequently deregulated in cancer. There is considerable interest in targeting the methylation machinery in tumor cells using nucleoside analogs of cytosine, such as 5-aza-2′-deoxycytidine (5-azadC). 5-azadC exerts its antitumor effects by reactivation of aberrantly hypermethylated growth regulatory genes and cytoxicity resulting from DNA damage. We sought to better characterize the DNA damage response of tumor cells to 5-azadC and the role of DNA methyltransferases 1 and 3B (DNMT1 and DNMT3B, respectively) in modulating this process. We demonstrate that 5-azadC treatment results in growth inhibition and G2 arrest—hallmarks of a DNA damage response. 5-azadC treatment led to formation of DNA double-strand breaks, as monitored by formation of γ-H2AX foci and comet assay, in an ATM (ataxia-telangiectasia mutated)-dependent manner, and this damage was repaired following drug removal. Further analysis revealed activation of key strand break repair proteins including ATM, ATR (ATM-Rad3-related), checkpoint kinase 1 (CHK1), BRCA1, NBS1, and RAD51 by Western blotting and immunofluorescence. Significantly, DNMT1-deficient cells demonstrated profound defects in these responses, including complete lack of γ-H2AX induction and blunted p53 and CHK1 activation, while DNMT3B-deficient cells generally showed mild defects. We identified a novel interaction between DNMT1 and checkpoint kinase CHK1 and showed that the defective damage response in DNMT1-deficient cells is at least in part due to altered CHK1 subcellular localization. This study therefore greatly enhances our understanding of the mechanisms underlying 5-azadC cytotoxicity and reveals novel functions for DNMT1 as a component of the cellular response to DNA damage, which may help optimize patient responses to this agent in the future.

scholarly journals Implication of Checkpoint Kinase-dependent Up-regulation of Ribonucleotide Reductase R2 in DNA Damage Response

2009 ◽  
Vol 284 (27) ◽  
pp. 18085-18095 ◽  
Author(s):  
Yong-Wei Zhang ◽  
Tamara L. Jones ◽  
Scott E. Martin ◽  
Natasha J. Caplen ◽  
Yves Pommier
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ribonucleotide Reductase ◽  
Checkpoint Kinase ◽  
Damage Response ◽  
Ribonucleotide Reductase R2

scholarly journals Site-Specific Phosphorylation of the DNA Damage Response Mediator Rad9 by Cyclin-Dependent Kinases Regulates Activation of Checkpoint Kinase 1

PLoS Genetics ◽  
2013 ◽  
Vol 9 (4) ◽  
pp. e1003310 ◽  
Author(s):  
Carla Manuela Abreu ◽  
Ramesh Kumar ◽  
Danielle Hamilton ◽  
Andrew William Dawdy ◽  
Kevin Creavin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Site Specific ◽  
Checkpoint Kinase ◽  
Cyclin Dependent Kinases ◽  
Checkpoint Kinase 1 ◽  
Damage Response

scholarly journals Anti-Tumor Effect of Inhibition of DNA Damage Response Proteins, ATM and ATR, in Endometrial Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1913 ◽  
Author(s):  
Makoto Takeuchi ◽  
Michihiro Tanikawa ◽  
Kazunori Nagasaka ◽  
Katsutoshi Oda ◽  
Yoshiko Kawata ◽  
...  
Keyword(s):  
Dna Damage ◽  
Endometrial Cancer ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Synthetic Lethality ◽  
Ataxia Telangiectasia Mutated ◽  
Checkpoint Kinase ◽  
Damage Response

While the incidence of endometrial cancer continues to rise, the therapeutic options remain limited for advanced or recurrent cases, and most cases are resistant to therapy. The anti-tumor effect of many chemotherapeutic drugs and radiotherapy depends on the induction of DNA damage in cancer cells; thus, activation of DNA damage response (DDR) pathways is considered an important factor affecting resistance to therapy. When some DDR pathways are inactivated, inhibition of other DDR pathways can induce cancer-specific synthetic lethality. Therefore, DDR pathways are considered as promising candidates for molecular-targeted therapy for cancer. The crosstalking ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 1 (ATR-Chk1) and ataxia telangiectasia mutated and Rad3 related and checkpoint kinase 2 (ATM-Chk2) pathways are the main pathways of DNA damage response. In this study, we investigated the anti-tumor effect of inhibitors of these pathways in vitro by assessing the effect of the combination of ATM or ATR inhibitors and conventional DNA-damaging therapy (doxorubicin (DXR), cisplatin (CDDP), and irradiation) on endometrial cancer cells. Both the inhibitors enhanced the sensitivity of cells to DXR, CDDP, and irradiation. Moreover, the combination of ATR and Chk1 inhibitors induced DNA damage in endometrial cancer cells and inhibited cell proliferation synergistically. Therefore, these molecular therapies targeting DNA damage response pathways are promising new treatment strategies for endometrial cancer.

scholarly journals Axitinib induces DNA damage response leading to senescence, mitotic catastrophe, and increased NK cell recognition in human renal carcinoma cells

Oncotarget ◽  
2015 ◽  
Vol 6 (34) ◽  
pp. 36245-36259 ◽  
Author(s):  
Maria Beatrice Morelli ◽  
Consuelo Amantini ◽  
Matteo Santoni ◽  
Alessandra Soriani ◽  
Massimo Nabissi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Renal Carcinoma ◽  
Nk Cell ◽  
Carcinoma Cells ◽  
Mitotic Catastrophe ◽  
Cell Recognition ◽  
Damage Response ◽  
Human Renal Carcinoma ◽  
Renal Carcinoma Cells

scholarly journals The Antiviral Agent Cidofovir Induces DNA Damage and Mitotic Catastrophe in HPV-Positive and -Negative Head and Neck Squamous Cell Carcinomas In Vitro

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 919 ◽  
Author(s):  
Femke Verhees ◽  
Dion Legemaate ◽  
Imke Demers ◽  
Robin Jacobs ◽  
Wisse Evert Haakma ◽  
...  
Keyword(s):  
Dna Damage ◽  
Head And Neck ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Squamous Cell ◽  
Antiviral Agent ◽  
Mitotic Catastrophe ◽  
Damage Response ◽  
Hnscc Cell

Cidofovir (CDV) is an antiviral agent with antiproliferative properties. The aim of our study was to investigate the efficacy of CDV in HPV-positive and -negative head and neck squamous cell carcinoma (HNSCC) cell lines and whether it is caused by a difference in response to DNA damage. Upon CDV treatment of HNSCC and normal oral keratinocyte cell lines, we carried out MTT analysis (cell viability), flow cytometry (cell cycle analysis), (immuno) fluorescence and western blotting (DNA double strand breaks, DNA damage response, apoptosis and mitotic catastrophe). The growth of the cell lines was inhibited by CDV treatment and resulted in γ-H2AX accumulation and upregulation of DNA repair proteins. CDV did not activate apoptosis but induced S- and G2/M phase arrest. Phospho-Aurora Kinase immunostaining showed a decrease in the amount of mitoses but an increase in aberrant mitoses suggesting mitotic catastrophe. In conclusion, CDV inhibits cell growth in HPV-positive and -negative HNSCC cell lines and was more profound in the HPV-positive cell lines. CDV treated cells show accumulation of DNA DSBs and DNA damage response activation, but apoptosis does not seem to occur. Rather our data indicate the occurrence of mitotic catastrophe.

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